The present invention relates to a class of indole derivatives which act on serotonin receptors (also known as 5-hydroxytryptamine or 5-HT receptors). More particularly, the invention concerns 1H-indole derivatives bearing an optionally substituted phenyl moiety at the 2-position of the indole ring system and a methylene-linked heterocyclic moiety at the 3-position of the indole ring system. These compounds are selective antagonists of the human 5-HT2A receptor and are therefore useful as pharmaceutical agents, especially in the treatment and/or prevention of adverse conditions of the central nervous system, including psychotic disorders such as schizophrenia.
Schizophrenia is a disorder which is conventionally treated with drugs known as neuroleptics. In many cases, the symptoms of schizophrenia can be treated successfully with so-called xe2x80x9cclassicalxe2x80x9d neuroleptic agents such as haloperidol. Classical neuroleptics generally are antagonists at dopamine D2 receptors.
Notwithstanding their beneficial antipsychotic effects, classical neuroleptic agents such as haloperidol are frequently responsible for eliciting acute extrapyramidal symptoms (movement disorders) and neuroendocrine (hormonal) disturbances. These side-effects, which plainly detract from the clinical desirability of classical neuroleptics, are believed to be attributable to D2 receptor blockade in the striatal region of the brain.
The compound (+)-xcex1-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)-ethyl]-4-piperidinemethanol (also known as MDL-100,907) is described in WO 91/18602. In preclinical studies, MDL-100,907 failed to induce catalepsy and failed to block apomorphine-induced stereotyped behaviour in animal models, strongly suggesting that this compound would be free from any liability to cause extrapyramidal side-effects. MDL-100,907 is currently undergoing clinical trials in schizophrenic patients and has demonstrated efficacy in a multicentre, placebo-controlled study for antipsychotic potential, with no neurological adverse effects. Pharmacologically, MDL-100,907 has been shown to be a potent antagonist of human 5-HT2A receptors, whilst being essentially devoid of activity at the human dopamine D2 receptor. It is accordingly believed that compounds which can interact selectively with the 5-HT2A receptor relative to the dopamine D2 receptor will display the beneficial level of antipsychotic activity associated with 5-HT2A receptor antagonism, whilst minimizing or even avoiding the extrapyramidal and other side-effects arising from an interaction with dopamine D2 receptors.
The present invention is described to compounds according to Formula (I) or a salt thereof which are selective antagonist of the human 5-HT2A receptor useful for treatment of adverse conditions of the central nervous system: 
The compounds of the present invention are potent antagonists of the human 5-HT2A receptor, and are accordingly of benefit in the treatment and/or prevention of psychotic disorders such as schizophrenia. The compounds of the invention display more effective binding to the human 5-HT2A receptor than to the human dopamine D2 receptor, and they can therefore be expected to manifest fewer side-effects than compounds which do not discriminate in their binding affinity as between 5-HT2A and D2 receptors.
By virtue of their potent human 5-HT2A receptor antagonist activity, the compounds of the present invention are also effective in the treatment of neurological conditions including depression, anxiety, panic disorder, obsessive-compulsive disorder, pain, sleep disorders such as insomnia, eating disorders such as anorexia nervosa, and dependency or acute toxicity associated with narcotic agents such as LSD or MDMA; and cardiovascular conditions including variant angina, Raynaud""s phenomenon, intermittent claudication, coronary and peripheral vasospasms, fibromyalgia, cardiac arrhythmias and thrombotic illness. They may also be generally of benefit in the inhibition of platelet aggregation, as well as in controlling the extrapyramidal symptoms associated with the administration of neuroleptic agents. They may further be effective in the lowering of intraocular pressure and may therefore be beneficial in treating glaucoma (cf. T. Mano et al. and H. Takaneka et al., Investigatiue Ophthalmology and Visual Science, 1995, Vol. 36, pages 719 and 734 respectively).
Being 5-HT2A receptor antagonists, the compounds of the present invention may also be beneficial in preventing or reducing the toxic symptoms associated with the intake of ergovaline in animals consuming Acremonium coenophialum infected tall fescue (cf. D. C. Dyer, Life Sciences, 1993, 53, 223-228).
The compounds according to the present invention are potent and selective 5-HT2A receptor antagonists having a human 5-HT2A receptor binding affinity (Ki) of 100 nM or less, typically of 50 nM or less and preferably of 10 nM or less. The compounds of the invention may possess at least a 10-fold selective affinity, suitably at least a 20-fold selective affinity and preferably at least a 50-fold selective affinity, for the human 5-HT2A receptor relative to the human dopamine D2 receptor.
The present invention provides a compound of formula I, or a salt thereof: 
wherein
A and B independently represent hydrogen, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, C1-6 alkyl or C1-6 alkoxy;
X and Y independently represent hydrogen, halogen, trifluoromethyl, trifluoromethoxy, C1-6 alkyl, C1-6 alkoxy or phenyl; and
Q represents a substituted five-, six- or seven-membered monocyclic heteroaliphatic ring containing one nitrogen atom and optionally one other heteroatom selected from oxygen, sulphur and nitrogen; or Q represents a substituted 6- to 11-membered bicyclic heteroaliphatic ring system which contains one nitrogen atom as the sole heteroatom; the moiety Q being linked to the remainder of the molecule via a carbon atom.
When Q represents a monocyclic heteroaliphatic ring, this is suitably a substituted pyrrolidine, piperidine, hexamethyleneimine, morpholine, thiomorpholine or piperazine ring linked through a carbon atom to the remainder of the molecule of formula I as depicted above.
When Q represents a bicyclic heteroaliphatic ring system, this is suitably a substituted 2-azabicyclo[2.2.2]octane or 2-azabicyclo[2.2.1]heptane ring system linked through a carbon atom to the remainder of the molecule of formula I as depicted above.
The moiety Q may typically be substituted by one, two or three substituents, suitably by one or two substituents. Preferably, the moiety Q is substituted, as appropriate, by the substituents R1, R2 and R3 as defined below.
Typical values for the moiety Q include the structures of formula Qa to Qm: 
in which the asterisk denotes the point of attachment to the remainder of the molecule;
Z represents oxygen, sulphur or Nxe2x80x94R1;
R1 and R2 independently represent hydrogen; or C1-6 alkyl, aryl(C1-6)alkyl or C3-7 heterocycloalkyl(C1-6)alkyl, any of which groups may be optionally substituted by one or more substituents; and
R3 represents hydrogen, halogen, C1-6 alkyl, hydroxy or C1-6 alkoxy; provided that at least one of R1, R2 and R3 is other than hydrogen.
Particular values for the moiety Q include the structures of formula Qa, Qb, Qc, Qd, Qe, Qg, Qk and Qm above.
Where it is other than hydrogen, the group R2 may be optionally substituted by one or more substituents. Suitably, the group R2 is unsubstituted, or substituted by one or two substituents. In general, the group R2 may be unsubstituted or monosubstituted. Examples of optional substituents on the group R2 include halogen, cyano, trifluoromethyl, hydroxy, C1-6 alkoxy, C1-6 alkylthio, C2-6 alkoxycarbonyl, C2-6 alkylcarbonyl, C1-6 alkylsulphonyl, arylsulphonyl, amino, C1-6 alkylamino, di(C1-6)alkylamino, di(C1-6)alkylaminomethyl, C2-6 alkylcarbonylamino, arylcarbonylamino, C2-6 alkoxycarbonylamino, N-(C1-6)alkyl-N-(C2-6)alkoxycarbonylamino, C1-6 alkylsulphonylamino, arylsulphonylamino, C1-6 alkylsulphonylaminomethyl, aminocarbonylamino, C1-6 alkylaminocarbonylamino, di(C1-6)alkylaminocarbonylamino, mono- or diarylaminocarbonylamino, pyrrolidinylcarbonylamino, piperidinylcarbonylamino, aminocarbonyl, C1-6 alkylaminocarbonyl, di(C1-6)alkylaminocarbonyl, aminosulphonyl, C1-6 alkylaminosulphonyl, di(C1-6)alkylaminosulphonyl, aminosulphonylmethyl, C1-6 alkylaminosulphonylmethyl and di(C1-6)alkylaminosulphonylmethyl.
A particular substituent on the group R2 is methoxy.
As used herein, the expression xe2x80x9cC1-6 alkylxe2x80x9d includes methyl and ethyl groups, and straight-chained or branched propyl, butyl, pentyl and hexyl groups. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl and tert-butyl. Derived expressions such as xe2x80x9cC1-6 alkoxyxe2x80x9d, xe2x80x9cC1-6 alkylthioxe2x80x9d and xe2x80x9cC1-6 alkylaminoxe2x80x9d are to be construed accordingly.
Typical aryl groups include phenyl and naphthyl, preferably phenyl.
The expression xe2x80x9caryl(C1-6)alkylxe2x80x9d as used herein includes benzyl, phenylethyl, phenylpropyl and naphthylmethyl, especially phenylethyl.
Typical heterocycloalkyl groups include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl and imidazolidinonyl groups.
A particular C3-7 heterocycloalkyl(C1-6)alkyl group is imidazolidinonylethyl.
The term xe2x80x9chalogenxe2x80x9d as used herein includes fluorine, chlorine, bromine and iodine, especially fluorine or chlorine.
For use in medicine, the salts of the compounds of formula I will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts.
Where the compounds according to the invention have at least one asymmetric centre, they may accordingly exist as enantiomers. Where the compounds according to the invention possess two or more asymmetric centres, they may additionally exist as diastereoisomers. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present invention.
Particular values for the substituent A in the compounds of formula I above include hydrogen, fluoro, trifluoromethyl, methyl and methoxy, especially hydrogen or fluoro.
Suitably, B represents hydrogen, fluoro, chloro, cyano, nitro, trifluoromethyl, trifluoromethoxy, methyl or methoxy, especially hydrogen.
Particular values for the substituent X include hydrogen, fluoro and methoxy, especially hydrogen.
Suitably, Y represents hydrogen, fluoro, chloro, bromo, methyl, methoxy or phenyl, especially hydrogen, fluoro or chloro. In one embodiment, Y represents hydrogen or fluoro.
Suitably, the moiety Q represents a group of formula Qc as depicted above.
Suitably, Z represents oxygen or Nxe2x80x94R1, especially Nxe2x80x94R1.
Suitably, R1 represents hydrogen or C1-6 alkyl, especially hydrogen or methyl. In one embodiment, R1 represents methyl. In another embodiment, R1 represents hydrogen.
Suitable values of R2 include hydrogen, methyl, ethyl, methoxyethyl, benzyl, phenylethyl and phenylpropyl. In one embodiment, R2 represents hydrogen. In another embodiment, R2 represents methyl.
Suitably, R3 represents hydrogen, halogen or C1-6 alkyl. Particular values of R3 include hydrogen, fluoro and methyl, typically hydrogen or methyl, and especially hydrogen.
A particular sub-class of compounds according to the invention is represented by the compounds of formula II, and salts thereof: 
wherein
Z1 represents oxygen, Nxe2x80x94R1 or CHxe2x80x94R3; and
A, B, X, Y, R1, R2 and R3 are as defined with reference to formula I above.
Suitably, Z1 represents oxygen or Nxe2x80x94R1.
Preferably, Z1 represents Nxe2x80x94R1.
Specific compounds within the scope of the present invention include:
3-(1-methylpiperidin-3-ylmethyl)-2-phenyl-1H-indole;
3-(1-methylpyrrolidin-3-ylmethyl)-2-phenyl-1H-indole;
3-(1-methylpyrrolidin-2(R)-ylmethyl)-2-phenyl-1H-indole;
3-(1-methylpyrrolidin-2(S)-ylmethyl)-2-phenyl-1H-indole;
2-methyl-3-(2-phenyl-1H-indol-3-ylmethyl)-2-azabicyclo[2.2.2]octane;
3-(2-methyl-2-azabicyclo[2.2.1]hept-3-ylmethyl)-2-phenyl-1H-indole;
3-(1,5-dimethyl-cis-pyrrolidin-2-ylmethyl)-2-phenyl-1H-indole;
3-(1,4-dimethylpiperazin-2(S)-ylmethyl)-2-phenyl-1H-indole;
7-chloro-3-(1,4-dimethylpiperazin-2(S)-ylmethyl)-2-phenyl-1H-indole;
3-(4-methylmorpholin-3-ylmethyl)-2-phenyl-1H-indole;
3-[1-(2-phenylethyl)piperidin-3-ylmethyl]-2-phenyl-1H-indole;
3-(1-benzylpyrrolidin-2-ylmethyl)-2-phenyl-1H-indole;
3-[1-(2-phenylethyl)pyrrolidin-2-ylmethyl]-2-phenyl-1H-indole;
2-phenyl-3-[1-(3-phenylpropyl)pyrrolidin-2(R)-ylmethyl]-1H-indole;
3-(1-benzylpyrrolidin-3-ylmethyl)-2-phenyl-1H-indole;
3-[1-(2-phenylethyl)pyrrolidin-3-ylmethyl]-2-phenyl-1H-indole;
3-(1-methylpiperidin-2(R)-ylmethyl)-2-phenyl-1H-indole;
3-(1-methylpiperidin-2(S)-ylmethyl)-2-phenyl-1H-indole;
3-(1-methylazepin-2(R)-ylmethyl)-2-phenyl-1H-indole;
3-(1-methylazepin-2(S)-ylmethyl)-2-phenyl-1H-indole;
3-(1-ethylpiperidin-2-ylmethyl)-2-phenyl-1H-indole;
3-[1-(2-methoxyethyl)piperidin-2-ylmethyl]-2-phenyl-1H-indole;
3-(1-benzylpiperidin-2-ylmethyl)-2-phenyl-1H-indole;
3-[1-(2-phenylethyl)piperidin-2-ylmethyl]-2-phenyl-1H-indole ;
2-(3-fluorophenyl)-6-fluoro-3-(4-methylpiperazin-2(S)-ylmethyl)-1H-indole;
2-(3-fluorophenyl)-6-fluoro-3-(1-methylpiperazin-2(S)-ylmethyl)-1H-indole; and salts thereof.
The invention also provides pharmaceutical compositions comprising one or more of the compounds according to this invention in association with a pharmaceutically acceptable carrier. Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto-injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. Alternatively, the compositions may be presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection. An erodible polymer containing the active ingredient may be envisaged. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. Favoured unit dosage forms contain from 1 to 100 mg, for example 1, 2, 5, 10, 25, 50 or 100 mg, of the active ingredient. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
In the treatment of schizophrenia, a suitable dosage level is about 0.01 to 250 mg/kg per day, preferably about 0.05 to 100 mg/kg per day, and especially about 0.05 to 5 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day.
If desired, the compounds according to this invention may be co-administered with another anti-schizophrenic medicament, for example one producing its effects via dopamine D2 and/or D4 receptor subtype blockade. In such circumstances, an enhanced anti-schizophrenic effect may be envisaged without a corresponding increase in side-effects such as those caused by, for example, D2 receptor subtype blockade; or a comparable anti-schizophrenic effect with reduced side-effects may alternatively be envisaged. Such co-administration may be desirable where a patient is already established on an anti-schizophrenic treatment regime involving conventional anti-schizophrenic medicaments. Suitable anti-schizophrenic medicaments of use in combination with the compounds according to the present invention include haloperidol, chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine, trifluoperazine, chloroprothixene, thiothixene, clozapine, olanzapine, pimozide, molindone, loxapine, sulpiride, risperidone, xanomeline, fananserin and ziprasidone, and pharmaceutically acceptable salts thereof.
The compounds according to the present invention wherein the moiety Q is substituted on the or each ring nitrogen atom may be prepared by a process which comprises attachment of the requisite substituent (e.g. the group of formula R2 as defined above) to a precursor compound of formula III: 
wherein A, B, X and Y are as defined above, and Q1 corresponds to a moiety of formula Q as defined above in which the or each ring nitrogen atom is unsubstituted; by conventional means including N-alkylation.
Where, for example, the moiety Q represents a structure of formula Qa to Qm as depicted above, attachment of the R2 moiety may conveniently be effected by standard alkylation techniques. One example thereof comprises treatment with an alkyl halide such as methyl iodide or ethyl bromide, an aryl(C1-6)alkyl halide such as benzyl bromide or 2-phenylethyl bromide, or a C3-7 heterocycloalkyl(C1-6)alkyl halide such as 2-(imidazolidin-2-on-1-yl)ethyl chloride, typically under basic conditions, e.g. potassium carbonate or caesium carbonate in isopropyl alcohol or N,N-dimethylformamide, optionally in the presence of sodium iodide. Another example comprises treatment with an aryl(C1-6)alkyl mesylate such as 2-phenylethyl methanesulphonate, typically in the presence of sodium carbonate and sodium iodide, in a suitable solvent such as 1,2-dimethoxyethane.
Alternatively, the R2 moiety may conveniently be attached by reductive alkylation, which may be accomplished in a single step, or as a two-step procedure. The single-step approach suitably comprises treating the required precursor compound with the appropriate aldehyde, e.g. formaldehyde, benzaldehyde or phenylacetaldehyde, in the presence of a reducing agent such as sodium cyanoborohydride. In a typical two-step procedure, for the preparation of a product wherein R2 corresponds to a group of formula xe2x80x94CH2R2a, a carboxylic acid derivative of formula R2axe2x80x94CO2H is condensed with the required precursor compound, suitably in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole hydrate, to afford a product wherein R2 represents xe2x80x94COR2a; the carbonyl group thereof can then be reduced, for example by treatment with diisobutylaluminium hydride, and the desired product thereby obtained.
The compounds of formula III above may in turn be prepared by reduction of a compound of formula IV: 
wherein A, B, X, Y and Q1 are as defined above.
Similarly, the compounds according to the invention may be prepared by a process which comprises reducing a compound of formula V: 
wherein A, B, X, Y and Q are as defined above.
Moreover, certain compounds according to the invention, in which the moiety Q is substituted on the or each ring nitrogen atom by a methyl group, may be prepared by a process which comprises reducing a compound of formula VI: 
wherein A, B, X and Y are as defined above, and Q2 corresponds to a moiety of formula Q as defined above in which the or each ring nitrogen atom is substituted by a benzyloxycarbonyl group.
Reduction of the compounds of formula IV, V and VI above is conveniently accomplished by treatment with a reducing agent such as lithium aluminium hydride, typically at an elevated temperature in an inert solvent, e.g. tetrahydrofuran.
The intermediates of formula IV above may be prepared from the appropriate precursor compound of formula VII: 
wherein A, B, X and Y are as defined above, and Q3 corresponds to a moiety of formula Q as defined above in which the or each ring nitrogen atom is substituted by an amino-protecting group Rp; by removal of the or each amino-protecting group Rp.
The amino-protecting group Rp referred to above is suitably benzyl, or a carbamoyl moiety such as benzyloxycarbonyl, either of which groups can conveniently be removed as necessary under transfer hydrogenation conditions utilising a hydrogenation catalyst such as palladium on charcoal in the presence of a hydrogen donor such as ammonium formate and/or 1,4-cyclohexadiene, typically in a lower alkanol solvent such as methanol or ethanol.
The intermediates of formula IV to VII above may be prepared by reaction of the appropriate compound of formula Qxe2x80x94COCl, Q1xe2x80x94COCl, Q2xe2x80x94COCl or Q3xe2x80x94COCl with two equivalents of a compound of formula VIII: 
wherein A, B, X, Y, Q, Q1, Q2 and Q3 are as defined above.
The intermediates of formula VIII above are suitably prepared by reacting a compound of formula IX: 
wherein A, B, X and Y are as defined above; with a Grignard reagent such as ethyl magnesium bromide.
In another procedure, the compounds according to the invention may be prepared by a process which comprises reacting a compound of formula X or an acid addition salt thereof, typically the hydrochloride salt, with a compound of formula XI: 
wherein A, B, X, Y and Q are as defined above.
The reaction between compounds X and XI, which is an example of the well-known Fischer indole synthesis, is suitably effected by stirring in ethanol at 25xc2x0 C., followed by heating in trifluoroacetic acid at 70xc2x0 C.
Where they are not commercially available, the starting materials of formula IX, X and XI may be prepared by procedures analogous to those described in the accompanying Examples, or by standard methods well known from the art.
It will be appreciated that any compound of formula I initially obtained from any of the above processes may, where appropriate, subsequently be elaborated into a further desired compound of formula I using techniques known from the art.
Where the above-described processes for the preparation of the compounds of use in the invention give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques such as preparative HPLC, or the formation of diastereomeric pairs by salt formation with an optically active acid, such as (xe2x88x92)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-1-tartaric acid, followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary.
During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.
The following Examples illustrate the preparation of compounds of use in the invention.
The compounds in accordance with this invention potently inhibit [3H]-ketanserin binding to the human 5-HT2A receptor expressed in clonal cell lines. Moreover, those compounds of the invention which have been tested display a selective affinity for the 5-HT2A receptor relative to the dopamine D2 receptor.
The compounds of the accompanying Examples were all found to possess a Ki value for displacement of [3H]-ketanserin from the human 5-HT2A receptor, when expressed in Chinese hamster ovary (CHO) clonal cell lines, of 100 nM or less.